Harnessing the Noncovalent Interactions of DNA Backbone with 2D Silicate Nanodisks To Fabricate Injectable Therapeutic Hydrogels

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Nano, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/acsnano.8b02434.Injectable hydrogels present several advantages over prefabricated scaffolds including ease of delivery, shear-thinning property, and broad applicability in the fields of drug delivery and tissue engineering. Here, we report an approach to develop injectable hydrogels with sustained drug release properties, exploiting the chemical nature of the DNA backbone and silicate nanodisks. A two-step gelation method is implemented for generating a combination of noncovalent network points, leading to a physically cross-linked hydrogel. The first step initiates the development of an interconnected structure by utilizing DNA denaturation and rehybridization mechanism to form hydrogen bonds between complementary base pairs of neighboring DNA strands. The anisotropic charge distribution of two-dimensional silicate nanodisks (nSi) makes them an active center in the second step of the gelation process. Silicate nanodisks create additional network points via attractive electrostatic interactions with the DNA backbone, thereby enhancing the mechanical resilience of the formulated hydrogel. The thermally stable hydrogels displayed an increase in elasticity and yield stress as a function of nSi concentration. They were able to form self-supporting structures post injection due to their rapid recovery after removal of cyclic stress. Moreover, the presence of nanosilicate was shown to modulate the release of a model osteogenic drug dexamethasone (Dex). The bioactivity of released Dex was confirmed from in vitro osteogenic differentiation of human adipose stem cells and in vivo bone formation in a rat cranial bone defect model. Overall, our DNA-based nanocomposite hydrogel obtained from a combination of noncovalent network points can serve as an injectable material for bone regeneration and carrier for sustained release of therapeutics

Controlling Adult Stem Cell Behavior Using Nanodiamond-Reinforced Hydrogel: Implication in Bone Regeneration Therapy

Nanodiamonds (NDs) have attracted considerable attention as drug delivery nanocarriers due to their low cytotoxicity and facile surface functionalization. Given these features, NDs have been recently investigated for the fabrication of nanocomposite hydrogels for tissue engineering. Here we report the synthesis of a hydrogel using photocrosslinkable gelatin methacrylamide (GelMA) and NDs as a three-dimensional scaffold for drug delivery and stem cell-guided bone regeneration. We investigated the effect of different concentration of NDs on the physical and mechanical properties of the GelMA hydrogel network. The inclusion of NDs increased the network stiffness, which in turn augmented the traction forces generated by human adipose stem cells (hASCs). We also tested the ability of NDs to adsorb and modulate the release of a model drug dexamethasone (Dex) to promote the osteogenic differentiation of hASCs. The ND-Dex complexes modulated gene expression, cell area, and focal adhesion number in hASCs. Moreover, the integration of the ND-Dex complex within GelMA hydrogels allowed a higher retention of Dex over time, resulting in significantly increased alkaline phosphatase activity and calcium deposition of encapsulated hASCs. These results suggest that conventional GelMA hydrogels can be coupled with conjugated NDs to develop a novel platform for bone tissue engineering

PRL3-zumab, a first-in-class humanized antibody for cancer therapy

Novel, tumor-specific drugs are urgently needed for a breakthrough in cancer therapy. Herein, we generated a first-in-class humanized antibody (PRL3-zumab) against PRL-3, an intracellular tumor-associated phosphatase upregulated in multiple human cancers, for unconventional cancer immunotherapies. We focused on gastric cancer (GC), wherein elevated PRL-3 mRNA levels significantly correlated with shortened overall survival of GC patients. PRL-3 protein was overexpressed in 85% of fresh-frozen clinical gastric tumor samples examined but not in patient-matched normal gastric tissues. Using human GC cell lines, we demonstrated that PRL3-zumab specifically blocked PRL-3(+), but not PRL-3(–), orthotopic gastric tumors. In this setting, PRL3-zumab had better therapeutic efficacy as a monotherapy, rather than simultaneous combination with 5-fluorouracil or 5-fluorouracil alone. PRL3-zumab could also prevent PRL-3(+) tumor recurrence. Mechanistically, we found that intracellular PRL-3 antigens could be externalized to become “extracellular oncotargets” that serve as bait for PRL3-zumab binding to potentially bridge and recruit immunocytes into tumor microenvironments for killing effects on cancer cells. In summary, our results document a comprehensive cancer therapeutic approach to specific antibody-targeted therapy against the PRL-3 oncotarget as a case study for developing antibodies against other intracellular targets in drug discovery

Updated Guidance Regarding The Risk ofAllergic Reactions to COVID-19 Vaccines and Recommended Evaluation and Management: A GRADE Assessment, and International Consensus Approach

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against \u3e 15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history

Search for continuous gravitational wave emission from the Milky Way center in O3 LIGO--Virgo data

We present a directed search for continuous gravitational wave (CW) signals emitted by spinning neutron stars located in the inner parsecs of the Galactic Center (GC). Compelling evidence for the presence of a numerous population of neutron stars has been reported in the literature, turning this region into a very interesting place to look for CWs. In this search, data from the full O3 LIGO--Virgo run in the detector frequency band $[10,2000]\rm~Hz$ have been used. No significant detection was found and 95$\%$ confidence level upper limits on the signal strain amplitude were computed, over the full search band, with the deepest limit of about $7.6\times 10^{-26}$ at $\simeq 142\rm~Hz$. These results are significantly more constraining than those reported in previous searches. We use these limits to put constraints on the fiducial neutron star ellipticity and r-mode amplitude. These limits can be also translated into constraints in the black hole mass -- boson mass plane for a hypothetical population of boson clouds around spinning black holes located in the GC.Comment: 25 pages, 5 figure

All-sky search for continuous gravitational waves from isolated neutron stars using Advanced LIGO and Advanced Virgo O3 data

We present results of an all-sky search for continuous gravitational waves which can be produced by spinning neutron stars with an asymmetry around their rotation axis, using data from the third observing run of the Advanced LIGO and Advanced Virgo detectors. Four different analysis methods are used to search in a gravitational-wave frequency band from 10 to 2048 Hz and a first frequency derivative from $-10^{-8}$ to $10^{-9}$ Hz/s. No statistically-significant periodic gravitational-wave signal is observed by any of the four searches. As a result, upper limits on the gravitational-wave strain amplitude $h_0$ are calculated. The best upper limits are obtained in the frequency range of 100 to 200 Hz and they are ${\sim}1.1\times10^{-25}$ at 95\% confidence-level. The minimum upper limit of $1.10\times10^{-25}$ is achieved at a frequency 111.5 Hz. We also place constraints on the rates and abundances of nearby planetary- and asteroid-mass primordial black holes that could give rise to continuous gravitational-wave signals.Comment: 23 main text pages, 17 figure

All-sky search for continuous gravitational waves from isolated neutron stars using Advanced LIGO and Advanced Virgo O3 data

We present results of an all-sky search for continuous gravitational waves which can be produced by spinning neutron stars with an asymmetry around their rotation axis, using data from the third observing run of the Advanced LIGO and Advanced Virgo detectors. Four different analysis methods are used to search in a gravitational-wave frequency band from 10 to 2048 Hz and a first frequency derivative from $-10^{-8}$ to $10^{-9}$ Hz/s. No statistically-significant periodic gravitational-wave signal is observed by any of the four searches. As a result, upper limits on the gravitational-wave strain amplitude $h_0$ are calculated. The best upper limits are obtained in the frequency range of 100 to 200 Hz and they are ${\sim}1.1\times10^{-25}$ at 95\% confidence-level. The minimum upper limit of $1.10\times10^{-25}$ is achieved at a frequency 111.5 Hz. We also place constraints on the rates and abundances of nearby planetary- and asteroid-mass primordial black holes that could give rise to continuous gravitational-wave signals